Osteosarcoma in a patient with Hutchinson-Gilford progeria.

King, Claire; Lemmer, J; Campbell, John R.; Atkins, Annette R.

doi:10.1136/jmg.15.6.481

Cited by 25 publications

(15 citation statements)

References 9 publications

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“…Increasing evidence suggests that A-type lamins act as tumor suppressors in part due to their regulation of the pRB pathway (Prokocimer et al, 2006;Dorner et al, 2007). Strikingly, an osteosarcoma (often associated with pRB inactivation in humans; Wadayama et al, 1994) was recently detected in an HGPS patient (King et al, 1978;Shalev et al, 2007). The LMNA mutation in this patient led not to progerin but rather to expression of an allele containing a smaller 35-amino acid deletion in C-terminus (Shalev et al, 2007).…”

Section: Discussionmentioning

confidence: 97%

Suppression of Proliferative Defects Associated with Processing-defective Lamin A Mutants by hTERT or Inactivation of p53

Kudlow

Stanfel

Burtner

et al. 2008

MBoC

116

118

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Hutchinson-Gilford progeria syndrome (HGPS) is a rare, debilitating disease with early mortality and rapid onset of aging-associated pathologies. It is linked to mutations in LMNA, which encodes A-type nuclear lamins. The most frequent HGPS-associated LMNA mutation results in a protein, termed progerin, with an internal 50 amino acid deletion and, unlike normal A-type lamins, stable farnesylation. The cellular consequences of progerin expression underlying the HGPS phenotype remain poorly understood. Here, we stably expressed lamin A mutants, including progerin, in otherwise identical primary human fibroblasts to compare the effects of different mutants on nuclear morphology and cell proliferation. We find that expression of progerin leads to inhibition of proliferation in a high percentage of cells and slightly premature senescence in the population. Expression of a stably farnesylated mutant of lamin A phenocopied the immediate proliferative defects but did not result in premature senescence. Either p53 inhibition or, more surprisingly, expression of the catalytic subunit of telomerase (hTERT) suppressed the early proliferative defects associated with progerin expression. These findings lead us to propose that progerin may interfere with telomere structure or metabolism in a manner suppressible by increased telomerase levels and possibly link mechanisms leading to progeroid phenotypes to those of cell immortalization. INTRODUCTIONThe nuclear lamins are broadly expressed and constitute the only intermediate filament proteins localized to the nucleus (Smith et al., 2005;Bridger et al., 2007;Dechat et al., 2008). Given the ability of lamins to form stable polymers resulting from coiled-coil interactions, they have typically been ascribed a structural role in the nucleus (McKeon et al., 1986;Lammerding et al., 2004Lammerding et al., , 2006; however, a variety of regulatory roles have also been proposed (Spann et al., 1997;Spann et al., 2002;Frock et al., 2006;Ivorra et al., 2006;Nitta et al., 2006Nitta et al., , 2007Scaffidi and Misteli, 2008). The two classes of lamins, B-type and A-type (of which lamin A and lamin C are the most prominent), have different patterns of expression. Whereas, isoforms of lamin B are expressed in all cells throughout development, lamins A and C (lamin A/C) are not expressed early in development. Instead, their expression begins during midgestation and is most prominent in differentiating and terminally differentiated cells (Rober et al., 1989).Mutations in LMNA (encoding all A-type lamins) are associated with at least 12 different human genetic disorders (Kudlow et al., 2007). Of these, at least three have features reminiscent of premature aging. The most common LMNAassociated premature aging-like syndrome, Hutchinson-Gilford progeria syndrome (HGPS), is often caused by a single nucleotide change in exon 11 of the LMNA gene (Cao and Hegele, 2003;De Sandre-Giovannoli et al., 2003;Eriksson et al., 2003). This mutation, generally referred to as G608G, is silent with regard to the coded a...

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Section: Discussionmentioning

confidence: 97%

Suppression of Proliferative Defects Associated with Processing-defective Lamin A Mutants by hTERT or Inactivation of p53

Kudlow

Stanfel

Burtner

et al. 2008

MBoC

116

118

View full text Add to dashboard Cite

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“…The first patient harbored a rare lamin A processing‐defective allele resulting in a smaller in‐frame deletion than classical HGPS (deletion of 35 residues as compared to 50 residues in HGPS) and was treated for osteosarcoma at age 9 [Shalev et al, ]. The second patient, whose genotype is not known, presented with many classical progeria signs and developed an osteosarcoma of the right chest wall; she succumbed to pneumonia at age 15 [King et al, ]. The predisposition to cancer in these two other patients with progeria and in this report in patients with LCPS may or may not share a common mechanism.…”

Section: Discussionmentioning

confidence: 99%

LMNA‐associated cardiocutaneous progeria: An inherited autosomal dominant premature aging syndrome with late onset

Kane

Lindsay

Judge

et al. 2013

American J of Med Genetics Pt A

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Hutchinson-Gilford Progeria Syndrome (HGPS) is a well-characterized premature aging disorder caused by mutations in LMNA, the gene encoding the nuclear scaffold proteins lamin A and C. In HGPS and related progerias, processing of prelamin A is blocked at a critical step mediated by the zinc metalloprotease ZMPSTE24. Emerging evidence indicates that LMNA-linked progerias can be grouped into two classes: 1) the processing-deficient, early onset “typical” progerias (e.g. HGPS), and 2) the processing-proficient “atypical” progeria syndromes (APS) that are later in onset. Here we describe a novel progeria syndrome with prominent cutaneous and cardiovascular manifestations belonging to the second class. We suggest the name LMNA-associated cardiocutaneous progeria syndrome (LCPS) for this disorder. Affected patients are normal at birth but undergo progressive cutaneous changes in childhood and die in middle age of cardiovascular complications, including accelerated atherosclerosis, calcific valve disease, and cardiomyopathy. In addition, the proband demonstrated cancer susceptibility, a phenotype rarely described for LMNA-based progeria disorders. The LMNA mutation that causes LCPS is a heterozygous missense mutation resulting in an amino acid substitution (D300G) in the coiled-coil domain of lamin A/C. In skin fibroblasts isolated from the proband, the processing and levels of lamin A and C are normal. However, nuclear morphology is aberrant and rescued by treatment with farnesyltransferase inhibitors (FTIs), as is also the case for HGPS and other laminopathies. Our findings advance knowledge of human LMNA progeria syndromes, and raise the possibility that typical and atypical progerias may converge upon a common mechanism to cause premature aging disease.

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“…There are also patients in whom no plaque formation in the coronaries is found [Reichel and Garcia‐Bunuel, 1970; Ishii, 1976; Shiraishi et al, 2001], or in whom the plaque formation and obstruction were very focal [Atkins, 1954; DeBusk, 1972; Baker et al, 1981]. A hypertrophy of myocardial cells occurs, often accompanied by interstitial fibrosis [Orrico and Strada, 1927; King et al, 1978; Baker et al, 1981; Shiraishi et al, 2001]. The aortic valve leaflets are thickened, especially at the base, and can be calcified [Gilford, 1897; Manschot, 1940; Makous et al, 1962; Reichel and Garcia‐Bunuel, 1970; DeBusk, 1972; Baker et al, 1981; Gamble, 1984; Stehbens et al, 1999].…”

Section: Cardiovascular Systemmentioning

confidence: 99%

Hutchinson–Gilford progeria syndrome: Review of the phenotype

Hennekam

2006

American J of Med Genetics Pt A

489

490

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Hutchinson–Gilford progeria syndrome (HGPS) is a rare but well known entity characterized by extreme short stature, low body weight, early loss of hair, lipodystrophy, scleroderma, decreased joint mobility, osteolysis, and facial features that resemble aged persons. Cardiovascular compromise leads to early demise. Cognitive development is normal. Data on 10 of our own cases and 132 cases from literature are presented. The incidence in the last century in the Netherlands was 1:4,000,000. Sex ratio was 1.2:1. Main first symptoms were failure to thrive (55%), hair loss (40%), skin problems (28%), and lipodystrophy (20%). Mean age at diagnosis was 2.9 years. Growth in weight was more disturbed than growth in height, and growth delay started already prenatally. Mean height > 13 years was 109.0 cm, mean weight was 14.5 kg. Osteolysis was wide‐spread but not expressed, except in the viscerocranium, and remained limited to membranous formed bone. Lipodystrophy is generalized, only intra‐abdominal fat depositions remain present. Cardiovascular problems are extremely variable, both in age of onset and nature. Stroke and coronary dysfunctioning are most frequent. Pathologic findings in coronaries and aorta resemble sometimes the findings in elderly persons, but can also be much more limited. Loss of smooth muscle cells seems the most important finding. Mean age of demise was 12.6 years. Patients can be subdivided in patients with classical HGPS, which follows an autosomal dominant pattern of inheritance, (almost) all cases representing spontaneous mutations, and in non‐classical progeria, in whom growth can be less retarded, scalp hair remains present for a longer time, lipodystrophy is more slowly progressive, osteolysis is more expressed except in the face, and survival well into adulthood is not uncommon. Pattern of inheritance of non‐classical progeria is most probably autosomal recessive. The cause of HGPS is an abnormally formed Lamin A, either directly by a mutated LMNA gene, or through abnormal posttranslational processing (ZMPSTE24 gene mutations). Of 34 LMNA mutations found in progeria patients, there were 26 classical p.G608G mutations (76%). Pathogenesis is most likely to follow several different pathways. Potential therapeutic strategies are developed along these lines and include RNA interference techniques and inhibition of the dominant‐negative influence of abnormally formed Lamin A on polymerization with normally formed Lamin A. © 2006 Wiley‐Liss, Inc.

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Osteosarcoma in a patient with Hutchinson-Gilford progeria.

Cited by 25 publications

References 9 publications

Suppression of Proliferative Defects Associated with Processing-defective Lamin A Mutants by hTERT or Inactivation of p53

Suppression of Proliferative Defects Associated with Processing-defective Lamin A Mutants by hTERT or Inactivation of p53

LMNA‐associated cardiocutaneous progeria: An inherited autosomal dominant premature aging syndrome with late onset

Hutchinson–Gilford progeria syndrome: Review of the phenotype

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